title: A classification of ductal plate malformations based on distinct pathogenic mechanisms of biliary dysmorphogenesis.
abstract: Ductal plate malformations (DPMs) are developmental anomalies considered to result from lack of ductal plate remodeling during bile duct morphogenesis. In mice, bile duct development is initiated by the formation of primitive ductal structures lined by two cell types, namely ductal plate cells and hepatoblasts. During ductal plate remodeling, the primitive ductal structures mature to ducts as a result from differentiation of the ductal plate cells and hepatoblasts to cholangiocytes. Here, we report this process is conserved in human fetal liver. These findings prompted us to evaluate how DPMs develop in three mouse models, namely mice with livers deficient in hepatocyte nuclear factor 6 (HNF6), HNF1β, or cystin-1 (cpk [congenital polycystic kidney] mice). Human liver from a patient with a HNF1B/TCF2 mutation, and from fetuses affected with autosomal recessive polycystic kidney disease (ARPKD) were also analyzed. Despite the epistatic relationship between HNF6, HNF1β, and cystin-1, the three mouse models displayed distinct morphogenic mechanisms of DPM. They all developed biliary cysts lined by cells with abnormal apicobasal polarity. However, the absence of HNF6 led to an early defect in ductal plate cell differentiation. In HNF1β-deficient liver, maturation of the primitive ductal structures was impaired. Normal differentiation and maturation but abnormal duct expansion was apparent in cpk mouse livers and in human fetal ARPKD.
  
  
  CONCLUSIONS
  DPM is the common endpoint of distinct defects initiated at distinct stages of bile duct morphogenesis. Our observations provide a new pathogenic classification of DPM.
authors.affiliation: de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Peggy
authors.initials: P
authors.lastname: Raynaud
authors.forename: Joshua
authors.initials: J
authors.lastname: Tate
authors.forename: Céline
authors.initials: C
authors.lastname: Callens
authors.forename: Sabine
authors.initials: S
authors.lastname: Cordi
authors.forename: Patrick
authors.initials: P
authors.lastname: Vandersmissen
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Carpentier
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Pierreux
authors.forename: Pierre
authors.initials: P
authors.lastname: Courtoy
authors.forename: Karin
authors.initials: K
authors.lastname: Dahan
authors.forename: Katty
authors.initials: K
authors.lastname: Delbecque
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lepreux
authors.forename: Marco
authors.initials: M
authors.lastname: Pontoglio
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Guay-Woodford
authors.forename: Frédéric P
authors.initials: FP
authors.lastname: Lemaigre
mesh_terms: D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000002:abnormalities* / Q000196:embryology* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D000013:Congenital Abnormalities / Q000145:classification* / Q000209:etiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D051539:Hepatocyte Nuclear Factor 1-beta / Q000378:metabolism; D051559:Hepatocyte Nuclear Factor 6 / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009024:Morphogenesis / Q000502:physiology*; D007690:Polycystic Kidney Diseases / Q000151:congenital / Q000378:metabolism / Q000503:physiopathology; D017044:Polycystic Kidney, Autosomal Recessive / Q000378:metabolism / Q000503:physiopathology
chemical_list: D015415:Biomarkers; C449819:Cys1 protein, mouse; C496495:HNF1B protein, human; D051559:Hepatocyte Nuclear Factor 6; C496496:Hnf1b protein, mouse; D008565:Membrane Proteins; C496606:Onecut1 protein, mouse; D051539:Hepatocyte Nuclear Factor 1-beta